9-72648654-AC-A

Variant names:

• chr9-72648654-AC-A
• NM_138691.3:c.9delC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138691.3(TMC1):​c.9delC​(p.Val6TyrfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.856

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-72648654-AC-A is Pathogenic according to our data. Variant chr9-72648654-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 3601926.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.9delC	p.Val6TyrfsTer33	frameshift_variant	Exon 5 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.19+32180delC		intron_variant	Intron 2 of 20		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.9delC	p.Val6TyrfsTer33	frameshift_variant	Exon 5 of 24	1	NM_138691.3	ENSP00000297784.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:1

Jan 09, 2025

Institute of Rare Diseases, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1;PM3_Supporting;PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-75263570;